CCR5 antagonists useful for treating AIDS

ABSTRACT

Compounds of the formula  
                 
 
     or a pharmaceutically acceptable salt or isomer thereof, wherein:  
     Q, X and Z are CH or N;  
     R, R 4 -R 7  and R 13  are H or alkyl;  
     R 1  is H, alkyl, fluoroalkyl, R 9 -arylalkyl, R 9 -heteroarylalkyl, alkyl—SO 2 —, cycloalkyl—SO 2 —, fluoroalkyl—SO 2 —, R 9 -aryl—SO 2 —, R 9 -heteroaryl—SO 2 —, N(R 22 )(R 23 )—SO 2 —, alkyl—C(O)—, cycloalkyl—C(O)—, fluoroalkyl—C(O)—, R 9 -aryl—C(O)—, NH-alkyl—C(O)— or R 9 -aryl—NH—C(O)—;  
     R 2  is H and R 3  is H, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, R 9 -aryl, R 9 -arylalkyl, R 9 -heteroaryl, or R 9 -heteroarylalkyl, and when X and Z are each CH, R 3  is alkoxy, R 9 -aryloxy, R 9 -heteroaryloxy, alkylC(O)O—, alkylaminoC(O)O—, alkylOC(O)NR 13 —, alkylOC(O)NR 13 — or alkylaminoC(O)NR 13 —;  
     or R 2  and R 3  together are ═O, ═NOR 10 , ═N—NR 11 R 12  or ═CH-alkyl;  
     R 8  is substituted phenyl, substituted heteroaryl, naphthyl, fluorenyl, diphenymethyl, alpha-substituted benzyl or alpha-substituted heteroarylmethyl;  
     R 9 -R 12  are as defined;  
     are disclosed for the treatment of HIV, solid organ transplant rejection, graft v. host disease, inflammatory diseases, atopic dermatitis, asthma, allergies or multiple sclerosis, as well as pharmaceutical compositions and combinations with antiviral or anti-inflammatory agents.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication 60/279,938, filed Mar. 29, 2001.

BACKGROUND

[0002] The present invention relates to piperidine derivatives useful asselective CCR5 antagonists, pharmaceutical compositions containing thecompounds, and methods of treatment using the compounds. The inventionalso relates to the use of a combination of a CCR5 antagonist of thisinvention and one or more antiviral or other agents useful in thetreatment of Human Immunodeficiency Virus (HIV). The invention furtherrelates to the use of a CCR-5 antagonist of this invention, alone or incombination with another agent, in the treatment of solid organtransplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis.

[0003] The global health crisis caused by HIV, the causative agent ofAcquired Immunodeficiency Syndrome (AIDS), is unquestioned, and whilerecent advances in drug therapies have been successful in slowing theprogression of AIDS, there is still a need to find a safer, moreefficient, less expensive way to control the virus.

[0004] It has been reported that the CCR5 gene plays a role inresistance to HIV infection. HIV infection begins by attachment of thevirus to a target cell membrane through interaction with the cellularreceptor CD4 and a secondary chemokine co-receptor molecule, andproceeds by replication and dissemination of infected cells through theblood and other tissue. There are various chemokine receptors, but formacrophage-tropic HIV, believed to be the key pathogenic strain thatreplicates in vivo in the early stages of infection, the principalchemokine receptor required for the entry of HIV into the cell is CCR5.Therefore, interfering with the interaction between the viral receptorCCR5 and HIV can block HIV entry into the cell. The present inventionrelates to small molecules which are CCR5 antagonists.

[0005] CCR-5 receptors have been reported to mediate cell transfer ininflammatory diseases such as arthritis, rheumatoid arthritis, atopicdermatitis, psoriasis, asthma and allergies, and inhibitors of suchreceptors are expected to be useful in the treatment of such diseases,and in the treatment of other inflammatory diseases or conditions suchas inflammatory bowel disease, multiple sclerosis, solid organtransplant rejection and graft v. host disease.

[0006] Piperidine derivatives which are muscarinic antagonists useful inthe treatment of cognitive disorders such as Alzheimer's disease aredisclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006; 5,952,349;and 5,977,138.

[0007] Piperidine and piperazine derivatives useful in the treatment ofAIDS are disclosed in WO 00/66559 and WO 00/66558.

[0008] A-M. Vandamme et al., Antiviral Chemistry & Chemotherapy, 9:187-203 (1998) disclose current clinical treatments of HIV-1 infectionsin man including at least triple drug combinations or so-called HighlyActive Antiretroviral Therapy (“HAART”); HAART involves variouscombinations of nucleoside reverse transcriptase inhibitors ( (“NRTI”),non-nucleoside reverse transcriptase inhibitors (“NNRTI”) and HIVprotease inhibitors (“PI”). In compliant drug-naive patients, HAART iseffective in reducing mortality and progression of HIV-1 to AIDS.However, these multidrug therapies do not eliminate HIV-1 and long-termtreatment usually results in multidrug resistance. Development of newdrug therapies to provide better HIV-1 treatment remains a priority.

SUMMARY OF THE INVENTION

[0009] The present invention relates to compounds useful as CCR5antagonist represented by the structural formula I

[0010] or a pharmaceutically acceptable salt or isomer thereof, wherein:

[0011] Q, X and Z are independently selected from the group consistingof CH and N, provided that one or both of Q and Z is N;

[0012] R, R⁴, R⁵, R⁶ and R⁷ are independently selected from the groupconsisting of H and (C₁-C₆)alkyl;

[0013] R¹ is H, (C₁-C₆)alkyl, fluoro-(C₁-C₆)alkyl-,R⁹-aryl(C₁-C₆)alkyl-, R⁹-heteroaryl-(C₁-C₆)alkyl-, (C₁-C₆)alkyl—SO₂—,(C₃-C₆)cycloalkyl—SO₂—, fluoro-(C₁-C₆)alkyl—SO₂—, R⁹-aryl—SO₂—,R⁹-heteroaryl—SO₂—, N(R²²)(R²³)—SO₂—, (C₁-C₆)alkyl—C(O)—,(C₃-C₆)cyclo-alkyl—C(O)—, fluoro-(C₁-C₆)alkyl—C(O)—, R⁹-aryl—C(O)—,NH—(C₁-C₆)alkyl—C(O)— or R⁹-aryl—NH—C(O)—;

[0014] R² is H or (C₁-C₆)alkyl, and R³ is H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-, (C₃-C₁₀)-cycloalkyl-,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-, R⁹-aryl, R⁹-aryl(C₁-C₆)-alkyl-,R⁹-heteroaryl, or R⁹-heteroaryl(C₁-C₆)alkyl-, provided that both X and Zare not each N;

[0015] or R² and R³ together are ═O, ═NOR¹⁰, ═N—NR¹¹R¹² or═CH(C₁-C₆)alkyl, provided that when one or both of X and Z is N, R² andR³ together are not ═CH(C₁-C₆)alkyl;

[0016] and when X and Z are each CH, R³ can also be (C₁-C₆)alkoxy,R⁹-aryloxy, R⁹-heteroaryloxy, (C₁-C₆)alkyl—C(O)O—,(C₁-C₆)alkyl—NH—C(O)O—, N((C₁-C₆)alkyl)₂—C(O)O—,(C₁-C₆)alkyl—C(O)—NR¹³—, (C₁-C₆)alkyl—O—C(O)—NR¹³—,(C₁-C₆)alkyl—NH—C(O)—NR¹³— or N((C₁-C₆)alkyl)₂—C(O)—NR¹³—;

[0017] R⁸ is (R¹⁴, R¹⁵, R¹⁶)-substituted phenyl, (R¹⁴, R¹⁵,R¹⁶)-substituted 6-membered heteroaryl, (R¹⁴, R¹⁵, R¹⁶)-substituted6-membered heteroaryl N-oxide, (R¹⁷, R¹⁸)-substituted 5-memberedheteroaryl, naphthyl, fluorenyl, diphenylmethyl,

[0018] R⁹ is 1, 2 or 3 substituents independently selected from thegroup consisting of H, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃,—OCF₃, CH₃C(O)—, —CN, CH₃SO₂—, CF₃SO₂— and —N(R )(R²²)(R²³);

[0019] R¹⁰ is H, (C₁-C₆)alkyl, fluoro(C₁-C₆)alkyl-,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-, hydroxy(C₂-C₆)alkyl-,(C₁-C₆)alkyl—O—(C₂-C₆)alkyl-, (C₁-C₆)alkyl—O—C(O)—(C₁-C₆)alkyl- orN(R²²)(R²³)—C(O)—(C₁-C₆)alkyl-;

[0020] R¹¹ and R¹² are independently selected from the group consistingof H, (C₁-C₆)alkyl and (C₃-C₁₀)cycloalkyl, or R¹¹and R¹² together areC₂-C₆ alkylene and form a ring with the nitrogen to which they areattached;

[0021] R¹⁴ and R¹⁵ are independently selected from the group consistingof (C₁-C₆)alkyl, halogen, —NR²²R²³, —OH, —CF₃, —OCH₃, —O—acyl and —OCF₃;

[0022] R¹⁶ is R¹⁴, hydrogen, phenyl, —NO₂, —CN, —CH₂F, —CHF₂, —CHO,—CH═NOR²⁴, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl,—N(R²⁴)CONR²⁵R²⁶, —NHCONH(chloro-(C₁-C₆)alkyl),—NHCONH((C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl), —NHCO(C₁-C₆)alkyl, —NHCOCF₃,—NHSO₂N(R²²)(R²³), —NHSO₂(C₁-C₆)alkyl, —N(SO₂CF₃)₂, —NHCO₂—(C₁-C₆)alkyl,C₃-C₁₀ cycloalkyl, —SR²⁷, —SOR²⁷, —SO₂R²⁷, —SO₂NH(R²²),—OSO₂(C₁-C₆)alkyl, —OSO₂CF₃, hydroxy(C₁-C₆)alkyl-, —CON R²⁴R²⁵,—CON(CH₂CH₂OCH₃)₂, —OCONH(C₁-C₆)alkyl, —CO₂R²⁴, —Si(CH₃)₃ or—B(OC(CH₃)₂)₂;

[0023] R¹⁷ is (C₁-C₆)alkyl, —N(R²²)(R²³) or R¹⁹-phenyl;

[0024] R¹³, R¹⁸, R²², R²³, R²⁴, R²⁵ and R²⁶ are independently selectedfrom the group consisting of H and (C₁-C₆)alkyl;

[0025] R¹⁹ is 1, 2 or 3 substituents independently selected from thegroup consisting of H, (C₁-C₆)alkyl, —CF₃, —CO₂R²⁵, —CN, (C₁-C₆)alkoxyand halogen;

[0026] R²⁰ and R²¹ are independently selected from the group consistingof H and (C₁-C₆)alkyl, or R²⁰ and R²¹ together with the carbon to whichthey are attached form a spiro ring of 3 to 6 carbon atoms; and

[0027] R²⁷ is (C₁-C₆)alkyl or phenyl.

[0028] Another aspect of the invention is a pharmaceutical compositionfor treatment of HIV comprising an effective amount of at least onecompound of formula I in combination with a pharmaceutically acceptablecarrier. Another aspect of the invention is a pharmaceutical compositionfor treatment of solid organ transplant rejection, graft v. hostdisease, arthritis, rheumatoid arthritis, inflammatory bowel disease,atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosiscomprising an effective amount of at least one compound of formula I incombination with a pharmaceutically acceptable carrier.

[0029] Yet another aspect of this invention is a method of treatment ofHIV comprising administering to a human in need of such treatment aneffective amount of at least one compound of formula I. Another aspectof the invention is a method of treatment of solid organ transplantrejection, graft v. host disease, arthritis, rheumatoid arthritis,inflammatory bowel disease, atopic dermatitis, psoriasis, asthma,allergies or multiple sclerosis comprising administering to a human inneed of such treatment an effective amount of at least one compound offormula I. Also contemplated is the use of at least one compound offormula I for the preparation of a medicament for the treatment of HIV,solid organ transplant rejection, graft v. host disease, arthritis,rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis,psoriasis, asthma, allergies or multiple sclerosis.

[0030] Still another aspect of this invention is the use of at least onecompound of formula I of this invention in combination with one or moreantiviral or other agents useful in the treatment of HumanImmunodeficiency Virus for the treatment of AIDS. Still another aspectof this invention is the use of at least one compound of formula I ofthis invention in combination with one or more other agents useful inthe treatment of solid organ transplant rejection, graft v. hostdisease, inflammatory bowel disease, rheumatoid arthritis or multiplesclerosis. The compound(s) of formula I and antiviral or other agentswhich are components of the combination can be administered in a singledosage form or they can be administered separately. Therefore, apharmaceutical composition comprising at least one compound of formula Iand one or more antiviral or other agents useful in the treatment of HIVis comtemplated, as well as a pharmaceutical composition comprising atleast one compound of formula I and one or more antiviral or otheragents useful in the treatment of solid organ transplant rejection,graft v. host disease, inflammatory bowel disease, rheumatoid arthritisor multiple sclerosis; a kit comprising separate dosage forms of theactives for treating HIV, solid organ transplant rejection, graft v.host disease, inflammatory bowel disease, rheumatoid arthritis ormultiple sclerosis is also contemplated.

DETAILED DESCRIPTION OF THE INVENTION

[0031] Preferred are compounds of formula I wherein Z is CH, and Q and Xare each N. Also preferred are compounds of formula I wherein R¹ isR⁹-aryl(C₁-C₆)alkyl-, R⁹-heteroaryl(C₁-C₆)alkyl-, (C₁-C₆)alkyl—SO₂—,(C₃-C₆)cycloalkyl—SO₂—, fluoro-(C₁-C₆)-alkyl—SO₂—, R⁹-aryl—SO₂—, orR⁹-aryl—NH—C(O)—. More preferably, R¹ is (C₁-C₆)alkyl—SO₂—,(C₁₃-C₆)cycloalkyl—SO₂— or R⁹-aryl—SO₂—. Preferably R² is hydrogen andR³ is (C₁-C₆)alkyl, R⁹-aryl, R⁹-aryl(C₁-C₆)-alkyl, R⁹-heteroaryl, orR⁹-heteroaryl(C₁-C₆)alkyl. When R² comprises an arylalkyl orheteroarylalkyl group, the alkyl portion of the arylalkyl orheteroarylalkyl preferably is methyl. R, R⁵ and R⁷ are preferablyhydrogen. R⁴ is preferably (C₁-C₆)alkyl, more preferably methyl, when Xis N; R⁴ is preferably H when X is CH. R⁶ is preferably —CH₃. R⁹ ispreferably H, halogen, (C₁-C₆)alkyl or (C₁-C₆)alkoxy. When R¹ or R³comprises an aryl or heteroaryl group, a preferred aryl group is phenyl,and preferred heteroaryl groups are thienyl, pyridyl and pyrimidyl.

[0032] In compounds of formula I, R⁸ is preferably (R¹⁴, R¹⁵,R¹⁶)-phenyl; (R¹⁴ , R¹⁵, R¹⁶)-pyridyl or an N-oxide thereof; or (R¹⁴,R¹⁵, R¹⁶)-pyrimidyl. When R⁸ is pyridyl, it is preferably 3- or4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R¹⁴ andR¹⁵ substituents are preferably attached to carbon ring members adjacentto the carbon joining the ring to the rest of the molecule and the R¹⁶substituent can be attached to any of the remaining unsubstituted carbonring members. Thus, structures of the preferred R⁸ substituents areshown as follows:

[0033] Preferred R¹⁴ and R¹⁵ substituents for compounds of formula Iare: (C₁-C₆)alkyl, especially methyl; halogen, especially chloro; and—NH₂; a preferred R¹⁶ substituent is hydrogen.

[0034] As used herein, the following terms are as defined below unlessotherwise indicated.

[0035] Alkyl (including the alkyl portions of alkoxy, alkylamino anddialkylamino) represents straight and branched carbon chains andcontains from one to six carbon atoms.

[0036] Fluoroalkyl represents an alkyl group as defined substituted byone or more fluorene atoms. Examples are —CH₂F, —CHF₂, —CF₃, —CH₂CF₃,—CF₂CF₃ and the like.

[0037] Hydroxyalkyl represents an alkyl group as defined substituted by1 to 3 hydroxy groups.

[0038] Alkenyl represents C₂-C₆ carbon chains having one or twounsaturated bonds, provided that two unsaturated bonds are not adjacentto each other.

[0039] Substituted phenyl means that the phenyl group can be substitutedat any available position on the phenyl ring.

[0040] Acyl means a radical of a carboxylic acid having the formulaalkyl—C(O)—, aryl—C(O)—, aralkyl—C(O)—, (C₃-C₇)cycloalkyl—C(O)—,(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl—C(O)—, and heteroaryl—C(O)—, whereinalkyl and heteroaryl are as defined herein.

[0041] Aryl is phenyl or naphthyl.

[0042] Heteroaryl represents cyclic aromatic groups of 5 or 6 atoms orbicyclic groups of 11 to 12 atoms having 1 or 2 heteroatomsindependently selected from O, S or N, said heteroatom(s) interrupting acarbocyclic ring structure and having a sufficient number of delocalizedpi electrons to provide aromatic character, provided that the rings donot contain adjacent oxygen and/or sulfur atoms. Nitrogen atoms can forman N-oxide. For 6-membered heteroaryl rings at R⁸, available carbonatoms can be substituted by R¹⁴, R¹⁵ or R¹⁶ groups. All regioisomers arecontemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical6-membered heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl and the N-oxides thereof. For 5-membered heteroaryl rings atR⁸, available carbon atoms can be substituted- by R¹⁷ or R¹⁸ groups.R⁹-substituted heteroaryl rings can be substituted on available carbonatoms by 1, 2 or 3 independently selected R⁹ groups. Typical 5-memberedheteroaryl rings are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl and isoxazolyl. 5-Membered rings having oneheteroatom can be joined through the 2- or 3- position; 5-membered ringshaving two heteroatoms are preferably joined through the 4-position.Bicyclic groups typically are benzo-fused ring systems derived from theheteroaryl groups named above, e.g. quinolyl, phthalazinyl,quinazolinyl, benzofuranyl, benzothienyl and indolyl.

[0043] Halogen represents fluoro, chloro, bromo and iodo.

[0044] A therapeutically effective amount of a CCR5 antagonist is anamount sufficient to lower HIV-1-RNA plasma levels.

[0045] One or more, preferably one to four, antiviral agents useful inanti-HIV-1 therapy may be used in combination with at least one (i.e.,1-4, preferably 1) CCR5 antagonist compound of the present invention.The antiviral agent or agents may be combined with the CCR5 antagonistin a single dosage form, or the CCR5 antagonist and the antiviral agentor agents may be administered simultaneously or sequentially as separatedosage forms. The antiviral agents contemplated for use in combinationwith the compounds of the present invention comprise nucleoside andnucleotide reverse transcriptase inhibitors, non-nucleoside reversetranscriptase inhibitors, protease inhibitors and other antiviral drugslisted below not falling within these classifications. In particular,the combinations known as HAART are contemplated for use in combinationwith the CCR5 antagonists of this invention.

[0046] The term “nucleoside and nucleotide reverse transcriptaseinhibitors” (“NRTI” s) as used herein means nucleosides and nucleotidesand analogues thereof that inhibit the activity of HIV-1 reversetranscriptase, the enzyme which catalyzes the conversion of viralgenomic HIV-1 RNA into proviral HIV-1 DNA.

[0047] Typical suitable NRTIs include zidovudine (AZT) available underthe RETROVIR tradename from Glaxo-Wellcome Inc., Research Triangle, N.C.27709; didanosine (ddI) available under the VIDEX tradename fromBristol-Myers Squibb Co., Princeton, N.J. 08543; zalcitabine (ddC)available under the HIVID tradename from Roche Pharmaceuticals, Nutley,N.J. 07110; stavudine (d4T) available under the ZERIT trademark fromBristol-Myers Squibb Co., Princeton, N.J. 08543; lamivudine (3TC)available under the EPIVIR tradename from Glaxo-Wellcome ResearchTriangle, N.C. 27709; abacavir (1592U89) disclosed in WO96/30025 andavailable under the ZIAGEN trademark from Glaxo-Wellcome ResearchTriangle, N.C. 27709; adefovir dipivoxil [bis(POM)-PMEA] available underthe PREVON tradename from Gilead Sciences, Foster City, Calif. 94404;lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitordisclosed in EP-0358154 and EP-0736533 and under development byBristol-Myers Squibb, Princeton, N.J. 08543; BCH-10652, a reversetranscriptase inhibitor (in the form of a racemic mixture of BCH-10618and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7V,4A7, Canada; emitricitabine [(−)-FTC] licensed from Emory Universityunder Emory Univ. U.S. Pat. No. 5,814,639 and under development byTriangle Pharmaceuticals, Durham, N.C. 27707; beta-L-FD4 (also calledbeta-L-D4C and named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene) licensedby Yale University to Vion Pharmaceuticals, New Haven Conn. 06511; DAPD,the purine nucleoside, (−)-beta-D-2,6,-diamino-purine dioxolanedisclosed in EP 0656778 and licensed by Emory University and theUniversity of Georgia to Triangle Pharmaceuticals, Durham, N.C. 27707;and lodenosine (FddA),9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, an acid stablepurine-based reverse transcriptase inhibitor discovered by the NIH andunder development by U.S. Bioscience Inc., West Conshohoken, Pa. 19428.

[0048] The term “non-nucleoside reverse transcriptase inhibitors”(“NNRTI”s) as used herein means non-nucleosides that inhibit theactivity of HIV-1 reverse transcriptase.

[0049] Typical suitable NNRTIs include nevirapine (BI-RG-587) availableunder the VIRAMUNE tradename from Boeh ringer Ingelheim, themanufacturer for Roxane Laboratories, Columbus, Ohio 43216; delaviradine(BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia& Upjohn Co., Bridgewater N.J. 08807; efavirenz (DMP-266) abenzoxazin-2-one disclosed in WO094/03440 and available under theSUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, Del.19880-0723; PNU-142721, a furopyridine-thio-pyrimide under developmentby Pharmacia and Upjohn, Bridgewater N.J. 08807; AG-1549 (formerlyShionogi # S-1153); 5-(3,5-dichlorophenyl)-thio4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbonatedisclosed in WO 96 /10019 and under clinical development by AgouronPharmaceuticals, Inc., LaJolla Calif. 92037-1020; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione)discovered by Mitsubishi Chemical Co. and under development by TrianglePharmaceuticals, Durham, N.C. 27707; and (+)-calanolide A (NSC-675451)and B, coumarin derivatives disclosed in NIH U.S. Pat. No. 5,489,697,licensed to Med Chem Research, which is co-developing (+) calanolide Awith Vita-invest as an orally administrable product.

[0050] The term “protease inhibitor” (“PI”) as used herein meansinhibitors of the HIV-1 protease, an enzyme required for the proteolyticcleavage of viral polyprotein precursors (e.g., viral GAG and GAG Polpolyproteins), into the individual functional proteins found ininfectious HIV-1. HIV protease inhibitors include compounds having apeptidomimetic structure, high molecular weight (7600 daltons) andsubstantial peptide character, e.g. CRIXIVAN (available from Merck) aswell as nonpeptide protease inhibitors e.g., VIRACEPT (available fromAgouron).

[0051] Typical suitable PIs include saquinavir (Ro 31-8959) available inhard gel capsules under the INVIRASE tradename and as soft gel capsulesunder the FORTOVASE tradename from Roche Pharmaceuticals, Nutley, N.J.07110-1199; ritonavir (ABT-538) available under the NORVIR tradenamefrom Abbott Laboratories, Abbott Park, Ill. 60064; indinavir (MK-639)available under the CRIXIVAN tradename from Merck & Co., Inc., WestPoint, Pa. 19486-0004; nelfnavir (AG-1343) available under the VIRACEPTtradename from Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020;amprenavir (141W94), tradename AGENERASE, a non-peptide proteaseinhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge,Mass. 02139-4211 and available from Glaxo-Wellcome, Research Triangle,N.C. under an expanded access program; lasinavir (BMS-234475) availablefrom Bristol-Myers Squibb, Princeton, N.J. 08543 (originally discoveredby Novartis, Basel, Switzerland (CGP-61755); DMP-450, a cyclic ureadiscovered by Dupont and under development by Triangle Pharmaceuticals;BMS-2322623, an azapeptide under development by Bristol-Myers Squibb,Princeton, N.J. 08543, as a 2nd-generation HIV-1 PI; ABT-378 underdevelopment by Abbott , Abbott Park, Ill. 60064; and AG-1549 an orallyactive imidazole carbamate discovered by Shionogi (Shionogi #S-1153) andunder development by Agouron Pharmaceuticals, Inc., LaJolla Calif.92037-1020.

[0052] Other antiviral agents include hydroxyurea, ribavirin, IL-2,IL-12, pentafuside and Yissum Project No. 11607. Hydroxyurea (Droxia), aribonucleoside triphosphate reductase inhibitor, the enzyme involved inthe activation of T-cells, was discovered at the NCI and is underdevelopment by Bristol-Myers Squibb; in preclinical studies, it wasshown to have a synergistic effect on the activity of didanosine and hasbeen studied with stavudine. IL-2 is disclosed in Ajinomoto EP-0142268,Takeda EP-0176299, and Chiron U.S. Pat. Nos. RE 33,653, 4,530,787,4,569,790, 4,604,377, 4,748,234, 4,752,585, and 4,949,314, and isavailable under the PROLEUKIN (aldesleukin) tradename from Chiron Corp.,Emeryville, Calif. 94608-2997 as a lyophilized powder for IV infusion orsc administration upon reconstitution and dilution with water; a dose ofabout 1 to about 20 million IU/day, sc is preferred; a dose of about 15million IU/day, sc is more preferred. IL-12 is disclosed in WO96/25171and is available from Roche Pharmaceuticals, Nutley, N.J. 07110-1199 andAmerican Home Products, Madison, N.J. 07940; a dose of about 0.5microgram/kg/day to about 10 microgram/kg/day, sc is preferred.Pentafuside (DP-178, T-20) a 36-amino acid synthetic peptide, isdisclosed in U.S. Pat. No. 5,464,933 licensed from Duke University toTrimeris which is developing pentafuside in collaboration with DukeUniversity; pentafuside acts by inhibiting fusion of HIV-1 to targetmembranes. Pentafuside (3-100 mg /day) is given as a continuous scinfusion or injection together with efavirenz and 2 PI's to HIV-1positive patients refractory to a triple combination therapy; use of 100mg/day is preferred. Yissum Project No.11607, a synthetic protein basedon the HIV -1 Vif protein, is under preclinical development by YissumResearch Development Co., Jerusalem 91042, Israel. Ribavirin,1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available fromICN Pharmaceuticals, Inc., Costa Mesa, Calif.; its manufacture andformulation are described in U.S. Pat. No. 4,211,771.

[0053] The term “anti-HIV-1 therapy” as used herein means any anti-HIV-1drug found useful for treating HIV-1 infections in man alone, or as partof multidrug combination therapies, especially the HAART triple andquadruple combination therapies. Typical suitable known anti-HIV-1therapies include, but are not limited to multidrug combinationtherapies such as (i) at least three anti-HIV-1 drugs selected from twoNRTIs, one PI, a second PI, and one NNRTI; and (ii) at least twoanti-HIV-1 drugs selected from NNRTIs and PIs. Typical suitableHAART-multidrug combination therapies include:

[0054] (a) triple combination therapies such as two NRTIs and one PI; or(b) two NRTIs and one NNRTI ; and (c) quadruple combination therapiessuch as two NRTIs, one PI and a second PI or one NNRTI. In treatment ofnaive patients, it is preferred to start anti-HIV-1 treatment with thetriple combination therapy; the use of two NRTIs and one PI is preferedunless there is intolerance to PIs. Drug compliance is essential. TheCD4⁺ and HIV-1-RNA plasma levels should be monitored every 3-6 months.Should viral load plateau, a fourth drug, e.g., one PI or one NNRTIcould be added. See the table below wherein typical therapies arefurther described: ANTI-HIV-1 MULTI DRUG COMBINATION THERAPIES A. TripleCombination Therapies 1. Two NRTIs¹ + one PI² 2. Two NRTIs¹ + one NNRTI³B. Quadruple Combination Therapies⁴ Two NRTIs + one PI + a second PI orone NNRTI C. ALTERNATIVES:⁵ Two NRTI¹ One NRTI⁵ + one PI² Two PIs⁶ ± oneNRTI⁷ or NNRTI³ One PI² + one NRTI^(7 + one NNRTI) ³

[0055] Agents known in the treatment of rheumatoid arthritis, transplantand graft v. host disease, inflammatory bowel disease and multiplesclerosis which can be administered in combination with the CCR5antagonists of the present invention are as follows:

[0056] solid organ transplant rejection and graft v. host disease:immune suppressants such as cyclosporine and Interleukin-10 (IL-10),tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;

[0057] inflammatory bowel disease: IL-10 (see U.S. Pat. No. 5,368,854),steroids and azulfidine;

[0058] rheumatoid arthritis: methotrexate, azathioprine,cyclophosphamide, steroids and mycophenolate mofetil;

[0059] multiple sclerosis: interferon-beta, interferon-alpha, andsteroids.

[0060] Certain CCR5 antagonist compounds of the invention may exist indifferent isomeric (e.g., enantiomers, diastereoisomers andatropisomers) forms. The invention contemplates all such isomers both inpure form and in admixture, including racemic mixtures.

[0061] Certain compounds will be acidic in nature, e.g. those compoundswhich possess a carboxyl or phenolic hydroxyl group. These compounds mayform pharmaceutically acceptable salts. Examples of such salts mayinclude sodium, potassium, calcium, aluminum, gold and silver salts.Also contemplated are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

[0062] Certain basic compounds also form pharmaceutically acceptablesalts, e.g., acid addition salts. For example, the pyrido-nitrogen atomsmay form salts with strong acid, while compounds having basicsubstituents such as amino groups also form salts with weaker acids.Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineraland carboxylic acids well known to those in the art. The salts areprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt in the conventional manner. The freebase forms may be regenerated by treating the salt with a suitabledilute aqueous base solution such as dilute aqueous NaOH, potassiumcarbonate, ammonia and sodium bicarbonate. The free base forms differfrom their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise equivalent to their respective free base forms forpurposes of the invention.

[0063] All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

[0064] Compounds of the invention can be made by the procedures known inthe art, for example by the procedures described in the followingreaction schemes, and by the methods described in the examples below.

[0065] The following solvents and reagents used in the general reactionschemes and the specific examples may be referred to herein by theabbreviations indicated: tetrahydrofuran (THF); methanol (MeOH); ethylacetate (EtOAc); trifluoroacetic anhydride (TFAA); dimethylformaldehyde(DMF); benzotriazole (Bt); 1-hydroxy-benzotriazole (HOBT); triethylamine(Et₃N); diethyl ether (Et₂O); tert-butoxy-carbonyl (BOC);N,N,N-diisopropylethylamine (iPr₂NEt); and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). Roomtemperature is rt. Additional abbreviations include: phenyl (Ph); methyl(Me); ethyl (Et); and acetyl (Ac).

[0066] Compounds of formula Ia wherein Q is N, Z is CH, X is N, R² is H,R³ is not H (but is otherwise is as defined above when R² is H), R⁶ ismethyl, and R¹ and R⁸ are as defined above are prepared according to thefollowing reaction Scheme A (R⁴ is shown as methyl, and R, R⁵ and R⁷ areshown as H, but compounds wherein R, R⁴, R⁵ and R⁷ are other variablescan be similarly prepared):

[0067] For the synthesis of compounds of formula Ia, the alcohol 1 isprotected and oxidized to the aldehyde 2. A solution of aldehyde 2,benzotriazole, and piperidino-piperazine 3 are heated in toluene orbenzene with removal of water. The solution is cooled and the solventremoved in vacuo. The adduct 4 is treated with a grignard reagent(R³MgX¹, wherein R³ is as defined above and X¹ is, e.g., Br or Cl) whichaffords a derivative of formula 5. The BOC group in 4 is removed (HCL),and the piperidine NH is coupled to an aryl acid to give amide 6. The4-methoxy benzyl group in 6 is removed by sequential treatment with TFAAand aqueous 1N NaOH. The piperidine can be functionalized with variousreagents, e.g., treatment with R¹SO₂Cl affords a compound of formula Iawherein R¹ is R¹—SO₂—.

[0068] Similar compounds wherein R⁶ is hydrogen can be prepared by usinga des-methyl piperidino-piperazine in place of compound 3.

[0069] Compounds of formula Ib wherein Q is N, Z is CH, X is N, R² andR³ are both H, and R¹ and R⁸ are as defined above are prepared accordingto the following reaction Scheme B (R⁴ and R⁶ are shown as methyl, andR⁵ and R⁷ are shown as H, but other definitions of R⁴-R⁷ can besimilarly prepared):

[0070] The aldehyde 2 is reacted with piperidino-piperazine 3 and sodiumtriacetoxy borohydride to obtain the derivative 7. This compound isprocessed similarly as above for 5 to obtain compounds of formula Ib.

[0071] Compounds of formula Ic wherein Q is N or CH, Z is N, X is CH, R²and R³ are both H, and R, R¹, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined aboveare prepared according to the following reaction Scheme C:

[0072] The aldehyde 8 can be reacted with Na(AcO)₃BH and piperazine(Q═N) or piperidine (Q═CH) 9 to obtain compound 10. After removal of theBoc group in 10 and standard amidation (EDC/HOBT/R⁸CO₂H or R⁸CO₂H) ofthe secondary amine, the amide of type Ic is prepared.

[0073] Compounds of formula Id wherein Q and Z are N, X is CH, R² is H,R³ is not H (but is otherwise is as defined above when R² is H), and R,R¹, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above are prepared according tothe following reaction Scheme D:

[0074] The aldehyde 8 is reacted with piperazine 14 and benzotriazole toform the adduct 15. The benzotriazole group in 15 is displaced by agrignard reagent (R³MgX¹) or organo-zinc reagent (R³ZnX¹) to obtain 16.Removal of the BOC group in 16, followed by standard coupling conditionsknow to those skilled in the art, gives the amide 17. The 4-methoxybenzyl group in 17 is removed and the resultant secondary amine isfunctionalized according to standard conditions to obtain compounds withthe general structure Id.

[0075] Piperidinyl compounds of formula Ie similar to piperazinylcompounds of formula Id are prepared according to Scheme E:

[0076] The aldehyde 8, piperidine 18, and benzotriazole are condensed toform the adduct 19. The benzotriazole (Bt) group is displaced in 19 togive the compound 20. Deprotection and standard amidation give thecompound Ie.

[0077] Compounds of formula If wherein Q is N, Z and X are CH, R² is H,R³ is optionally substituted phenoxy or pyridyloxy, and R, R¹, R⁴, R⁵,R⁶, R⁷ and R⁸ are as defined above are prepared according to thefollowing reaction Scheme F:

[0078] The aldehyde 8 is reacted with the grignard reagent to give thealcohol 21. The alcohol 21 is oxidized to the ketone 22. The N-methylgroup in 22 is removed with 1-chloroethyl chloroformate to give thepiperidine 23. Reduction of 23 followed by reductive alkylation of thepiperdine gives the derivative 24. The aryloxy (and heteroaryloxy)compounds 25 are obtained by treatment of alcohol 24 with phenyl orpyridyl halides in the presence of a base. The Boc protected amine in 25is deprotected, and the corresponding piperidine is subjected tostandard amidation conditions (R⁸COOH, EDCI or DEC, and HOBT, orR⁸C(O)Cl). The 4-methoxy benzyl group in 26 is removed, and the freepiperidinyl NH is derivatized with alkyl halides, acyl chorides, alkylchloroformates, isocyanides, alkyl sulfonyl halides, aryl sulfonylhalides, and reductive alkylation methods (Na(AcO)₃BH/aldehyde orketone) to obtain compounds of formula If.

[0079] Compounds of formula Ig wherein Q is N, Z and X are CH, R² is H,R³is alkyl—C(O)O—, alkyl—NH—C(O)O— or —OC(O)—N(alkyl)₂, and R, R¹, R⁴,R⁵, R⁶, R⁷ and R⁸ are as defined above are prepared according to thefollowing reaction Scheme G:

[0080] The hydroxyl group in 24 is derivatized using alkyl halides, acylchlorides, alkyl chloroformates, and isocyanides to give compounds 28.Deprotection/amidation of 27 gives the amide 28. Deprotection of thebenzyl group in 28 and derivatization of the piperidine give thecomounds of formula Ig.

[0081] Compounds of formula Ih wherein Q is N, Z and X are CH, R² is H,R³ is alkyl—C(O)—NH—, alkyl—NH—C(O)NH— or —NH—C(O)—N(alkyl)₂, and R, R¹,R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above are prepared according to thefollowing reaction Scheme H:

[0082] The alcohol 24 is oxidized (DMSO/oxalyl chloride, Swernconditions) to the ketone 29. Deprotection/standard amidation of 29gives the amide 30. The ketone 30 is condensed with CH₃ONH₂ HCl to givean oxime. The oxime is reduced with BH₃ S(CH₃)₂ to obtain the amine 31.The amine 31 is reacted with chloroformates, acid chlorides, orisocyanides to furnish carbamates, esters, and ureas, respectively, offormula 32 wherein G is as defined above. Deprotection of the benzylgroup in 32 and derivatization of the piperidine give the comounds offormula Ih.

[0083] Oximes of formula Ii wherein Q is N, Z and X are CH, R² andR³together are ═NOR¹⁰, and R¹⁰, R, R¹, R⁴, R⁵, R⁶, R⁷ and R⁸ are asdefined above are prepared according to the following reaction Scheme I:

[0084] The ketone 30 is condensed with subsituted hydroxylamines toobtain the oximes 33. The 4-methoxy group in 33 is removed andfunctionalized as previously described to obtain the comounds of formulaIi.

[0085] Compounds of formula Ij wherein Q, Z and X are each N, R² and R³together are ═O, and R, R¹, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined aboveare prepared according to the following reaction Scheme J:

[0086] The piperidino-piperazine 34 is sequentially reacted withN,N′-disuccinimidyl carbonate (DSC) and piperazine 14 to obtain the urea35. The Boc derivative 35 is processed to 36 and Ij using conditionsdescribed in Scheme A.

[0087] Compounds of formula Ik wherein Q is N or CH, Z and X are each N,R² and R³ together are ═NH, and R, R¹, R⁴, R⁵, R⁶, R⁷ and R⁸ are asdefined above are prepared by several methods, for example according tothe following reaction Scheme K:

[0088] The piperidino-piperazine 34 can be converted into the guanidine39 by the method shown above. The guanidine 39 can be converted into theamides of formula Ik by the methods described in Scheme A.

[0089] Compounds useful in this invention are exemplified by thefollowing preparative examples, which should not be construed to limitthe scope of the disclosure. Alternative mechanistic pathways andanalogous structures within the scope of the invention may be apparentto those skilled in the art.

EXAMPLE 1

[0090]

[0091] Step 1

[0092] The alcohol 1 (2.0 g, 17 mmol), 4-methoxy benzaldehyde (2.5 ml,21 mmol), and Na(AcO)₃BH (4.4 g, 21 mmol) were taken up in CH₂Cl₂ (50ml) and stirred at 25 ° C. for 22 h. The solution was diluted withCH₂Cl₂ and washed with aqueous 1N NaOH. The aqueous layer was extractedwith CH₂Cl₂. The combined organic layers were dried (Na₂SO₄), filteredand concentrated. The residue was partitioned between Et₂O and 1 M HCl.The acidic, aqueous layer was extracted with Et₂O. The aqueous layer wascooled to 0° C. Solid NaOH pellets were added until the pH=11-12. Thebasic, aqueous layer was extracted with CH₂Cl₂. The CH₂Cl₂ layers weredried (Na₂SO₄), filtered, and concentrated to obtain the benzylprotected piperdino-alcohol (2.92 g, 73%).

[0093] DMSO (1.3 ml, 19 mmol) was taken up in CH₂Cl₂ (80 ml), and theresulting solution was cooled to −40° C. (CO₂/CH₃CN). Oxalyl chloride(1.6 ml, 19 mmol) was added slowly to the solution at −40° C. Thesolution was allowed to stir at 40° C. for 0.5 h. TheN-(4-methoxybenzyl)-piperdino-alcohol (2.92 g, 12 mmol) was added as asolution in CH₂Cl₂ (15 ml) to the reaction mixture at −40° C. Theresulting solution was stirred at −40° C. for 0.5 h. Et₃N (5.2 ml, 37mmol) was added to the solution at −40° C. The resulting white slurrywas stirred tor 20 min. at that temperature. The mixture was dilutedwith CH₂Cl₂ and washed with aqueous 1 N NaOH. The aqueous layer wasextracted with CH₂Cl₂. The combined CH₂Cl₂ layers were dried (Na₂SO₄),filtered, and concentrated to obtain the aldehyde 2 as a yellow oil (2.8g, 97%).

[0094] Step 2

[0095] The aldehyde 2 (392 mg, 1.68 mmol), piperidino-piperazine 3 (500mg, 1.68 mmol), and benzotriazole (200 mg, 1.68 mmol) were taken up intoluene (20 ml) and heated at reflux with removal of water (Dean-Starktrap). After 2 h, the solution was cooled and concentrated to obtain 1.0g (100%) of the benzotriazole adduct 4 as a light brown gum.

[0096] The product of Step 2 (300 mg, 0.48 mmol) was taken up in THF (4ml) under an atmosphere of N₂. A solution of PhMgBr (0.4 ml, 3.0 M inEt₂O) was added to the solution at 25° C. The solution was stirred atthat temperature for 2 h. The reaction mixture was partitioned betweenEtOAc and sat. NH₂Cl. The aqeuous layer was extracted with EtOAc. Thecombined EtOAc layers were washed with brine and dried (Na₂SO₄).Filtration and concentration furnished a yellow oil. The material waspurified by preparative thin-layer chromatography (2/1 hexanes/acetone,SiO₂) to obtain 207 mg (73%) of compound 5 a as a yellow oil.

[0097] Compound 5 a (200 mg, 0.34 mmol) and 4.0 M HCl in dioxane (1 ml)were taken up in MeOH (5 ml) and stirred at 25° C. for 2 h. The solutionwas concentrated to give 189 mg (93%) of the deprotected piperidine asthe tri-hydrochloride salt.

[0098] The salt (189 mg, 0.32 mmol), EDC (92 mg, 0.48 mmol), HOBT (65mg, 0.48 mmol), 4,6-dimethyl-3-pyrimidine carboxylic acid (73 mg. 0.48mmol), iPr₂NEt (0.4 ml, 2.24 mmol) were taken up in DMF (5 ml) andstirred at 25° C. for 17 h. The solution was partitioned between EtOAcand 1 N NaOH. The aqueous layer was extracted with EtOAc. The combinedEtOAc layers were washed with brine and dried (Na₂SO₄). Filtration andconcentration gave the crude product. Purification by preparativethin-layer chromatography (95/5 EtOAc/Et₃N, SiO₂) gave 144 mg (72%) ofamide 6a as a colorless oil. HRMS (MH⁺) found: 625.4222.

[0099] Compound 6 a (129 mg, 0.21 mmol) and iPr₂NEt (0.11 ml, 0.63 mmol)were taken up in CH₂Cl₂ (6 ml). TFAA (0.080 ml, 0.31 mmol) was added tothe solution. The solution was stirred at 25° C. for 0.5 h, thenconcentrated. The residue was taken up in MeOH, and 1 N NaOH was addedto the solution. The solution was stirred at 25° C. for 2.5 h, thenconcentrated. The residue was partitioned between CH₂Cl₂ and 1 N NaOH.The aqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried (Na₂SO₄), filtered, and concentrated to obtain a mixture ofexample 6b and 4-methoxy benzyl alcohol. Example 6b was purified bycrystallization of the corresponding HCl salt. HRMS (MH⁺) found:505.3661.

[0100] The free base of example 6 b (42 mg, 0.08 mmol) and MeSO₂Cl(0.020 ml) were partitioned between CH₂Cl₂ and 1 N NaOH. The solutionwas stirred at 25° C. for 4 h. The layers were separated, and theaqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by thin layer chromatography (95/5 EtOAc/Et₃N, SiO₂) to givethe title compound as a colorless oil. The bis-HCl salt was formed bydissolving the free-base in EtOAc followed by trituration with 2 M HClin Et₂O. HRMS (MH⁺)found: 583.3425.

[0101] Using a similar procedure and the appropriate reagents, compoundsof the structure

were prepared, wherein R¹, R³ and R⁶ are as defined in the followingtable: HRMS Ex. R¹ R³ R⁶ (MH⁺) found 1A 4-CH₃OC₆H₄CH₂ 4-CF₃C₆H₅ CH₃693.4112 1B H 4-CF₃C₆H₅ CH₃ 573.3637 1C CH₃SO₂ 4-CF₃C₆H₅ CH₃ 651.3311 1D4-CH₃OC₆H₄CH₂ CH₂CH₂CH₃ CH₃ 591.4386 1E 4-CH₃OC₆H₄CH₂ CH(CH₃)₂ CH₃591.4392 1F 4-CH₃OC₆H₄CH₂ CH₂C₆H₅ CH₃ 639.4399 1G 4-CH₃OC₆H₄CH₂ CH₃ CH₃563.4079 1H 4-CH₃OC₆H₄CH₂ CH₂CH₃ CH₃ 577.4226 1I H CH₂CH₂CH₃ CH₃471.3802 1J CH₃SO₂ CH₂CH₂CH₃ CH₃ 549.3580 1K 4-CH₃OC₆H₄CH₂ cyclopentylCH₃ 617.4543 1L H CH(CH₃)₂ CH₃ 471.3815 1M CH₃SO₂ CH(CH₃)₂ CH₃ 549.35801N 4-CH₃C₆H₄SO₂ CH(CH₃)₂ CH₃ 625.3917 1O 4-CH₃C₆H₄SO₂ CH₂CH₂CH₃ CH₃625.3895 1P CH₃SO₂ cyclopentyl CH₃ 575.3746 1Q 4-CH₃C₆H₄SO₂ cyclopentylCH₃ 651.4055 1R H cyclopentyl CH₃ 497.3966 1S 4-CH₃C₆H₄SO₂ C₆H₅ CH₃659.3752 1T EtNHC(O) C₆H₅ CH₃ 576.4028 1U C₆H₅NHC(O) C₆H₅ CH₃ 624.40271V H cyclohexyl CH₃ 511.4120 1W 4-CH₃OC₆H₄CH₂ CH₂CH₂CH₃ H 577.4230 1X4-CH₃OC₆H₄CH₂ CH₂C₆H₅ H 625.4221 1Y 4-CH₃OC₆H₄CH₂ C₆H₅ H 611.4089 1Z4-CH₃OC₆H₄SO₂ C₆H₅ CH₃ 675.3684 1AA 3-Cl—C₆H₄SO₂ C₆H₅ CH₃ 679.3188 1ABCH₃SO₂ CH₂C₆H₅ CH₃ 597.3583 1AC CH₃ C₆H₅ CH₃ 519.3815 1AD 3-Cl—C₆H₄SO₂CH₂C₆H₅ CH₃ 693.3345 1AE CH₃CH₂SO₂ CH₂C₆H₅ CH₃ 611.3737 1AF4-CH₃OC₆H₄SO₂ 4-F—C₆H₄ CH₃ 693.3609 1AG CH₃SO₂ 4-F—C₆H₄ CH₃ 601.3326 1AH3-Cl—C₆H₄SO₂ 4-F—C₆H₄ CH₃ 697.3112 1AI 4-CH₃OC₆H₄CH₂ 3-F—C₆H₄ CH₃643.4142 1AJ CF₃C(O) 4-F—C₆H₄CH₂ CH₃ 633.3552 1AK CH₃SO₂ 3-F—C₆H₄ CH₃601.3326 1AL 3-Cl—C₆H₄SO₂ 3-F—C₆H₄ CH₃ 697.3105 1AM 4-CH₃OC₆H₄SO₂3-F—C₆H₄ CH₃ 693.3609 1AN CH₃SO₂ 4-F—C₆H₄CH₂ CH₃ 615.3482 1AO3-Cl—C₆H₄SO₂ 4-F—C₆H₄CH₂ CH₃ 711.3250 1AP 4-CH₃OC₆H₄SO₂ 4-F—C₆H₄CH₂ CH₃707.3751 1AQ 4-CH₃OC₆H₄CH₂ 2-thienyl CH₃ 631.3805 1AR CF₃CH₂SO₂ C₆H₅ CH₃651.3201 1AS CF₃SO₂ C₆H₅ CH₃ 637.3156 1AT 4-CH₃OC₆H₄CH₂ 3-thienyl CH₃631.3784 1AU 3-Cl—C₆H₄SO₂ 2-thienyl CH₃ 685.2768 1AV 4-CH₃OC₆H₄SO₂2-thienyl CH₃ 681.3266 1AW CH₃SO₂ 2-thienyl CH₃ 589.3002 1AX CH₃SO₂3-thienyl CH₃ 589.3002 1AY 3-Cl—C₆H₄SO₂ 3-thienyl CH₃ 685.2750 1AZ4-F—C₆H₄SO₂ CH₂C₆H₅ CH₃ 677.3633 1BA 2-thienyl-SO₂ CH₂C₆H₅ CH₃ 665.33171BB C₆H₅SO₂ CH₂C₆H₅ CH₃ 653.3748 1BC CF₃SO₂ CH₂C₆H₅ CH₃ 651.3317 1BDCF₃CH₂SO₂ CH₂C₆H₅ CH₃ 665.3449 1BE (CH₃)₂NSO₂ CH₂C₆H₅ CH₃ 626.3859 1BFcyclopropyl-SO₂ 3-F—C₆H₄ CH₃ 627.3503 1BG 4-F—C₆H₄SO₂ 3-F—C₆H₄ CH₃681.3406 1BH 4-CH₃OC₆H₄CH₂ n-Butyl CH₃ 605.4556 1BI 3-Cl—C₆H₄SO₂ n-ButylCH₃ 659.3501 1BJ 4-CH₃OC₆H₄SO₂ n-Butyl CH₃ 655.4009 1BK 3-Cl—C₆H₄SO₂3-pyridyl CH₃ 680.3166 1BL 4-CH₃OC₆H₄SO₂ 3-pyridyl CH₃ 676.3637 1BM3-Cl—C₆H₄SO₂ 2-pyridyl CH₃ 680.3160 1BN cyclopropyl-SO₂ C₆H₅ CH₃609.3598 1BO 4-CH₃OC₆H₄CH₂ 2-pyrimidyl CH₃ 627.4128 1BP CH₃CH₂SO₂ C₆H₅CH₃ 597.3598 1BQ CH₃CH₂CH₂SO₂ C₆H₅ CH₃ 611.3749 1BR i-propyl-SO₂ C₆H₅CH₃ 611.3749 1BS CH₃C(O) C₆H₅ CH₃ 547.3768 1BT CH₃SO₂ 2-pyrimidyl CH₃585.3343 1BU cyclopropyl-C(O) C₆H₅ CH₃ 573.3923 1BV CH₃CH₂C(O) C₆H₅ CH₃561.3928 1BW i-propyl-C(O) C₆H₅ CH₃ 575.4075 1BX 3-Cl—C₆H₄SO₂ 4-pyridylCH₃ 680.3133 1BY 4-CH₃OC₆H₄CH₂ 3,5-difluorophenyl CH₃ 661.4035 1BZcyclopropyl-SO₂ 3,5-difluorophenyl CH₃ 645.3388 1CA CH₃SO₂ cyclohexylCH₃ 589.3904

[0102] Details of the preparation of 1BF:

[0103] The product of Example 1, Step 2 (1.0 g, 1.6 mmol) was taken upin THF (10 ml) under an atmosphere of N₂ and a solution of3-fluorophenylmagnesium bromide (13 ml, 0.5 M in Et₂O) was added at 25°C. The solution was stirred at 25° C. for 6 h. The reaction mixture waspoured into a separatory funnel containing 25% aqueous sodium citrate.The aqeuous layer was extracted with EtOAc, the combined EtOAc layerswere washed with brine and dried (Na₂SO₄). Filtration and concentrationfurnished a yellow oil. The material was purified by flashchromatography (3/1 hexanes/acetone, SiO₂) which gave 640 mg (66%) ofcompound 5b as a yellow oil.

[0104] 5b (640 mg, 1.05 mmol) was deprotected according to the procedureof Example 1, Step 4 to obtain the deprotected piperidine. Thepiperidine (533 mg, 0.32 mmol), EDC (400 mg, 0.48 mmol), HOBT (280 mg,0.48 mmol), 4,6-dimethyl-3-pyrimidine-5-carboxylic acid (240 mg. 0.48mmol) and iPr₂NEt (0.72 ml, 2.24 mmol) were taken up in DMF (5 ml) andsubjected to conditions described above in Step 4 to furnish 414 mg(62%) of 6b as a yellow oil.

[0105] 6c (400 mg, 0.62 mmol) was treated according to the procedure ofExample 1, Step 5, to obtain 6d. The free base 6d (0.07 g, 0.13 mmol),cyclopropylsulfonyl chloride (0.02 g, 0.14 mmol) and Et₃N (0.091 ml)were taken up in CH₂Cl₂ and the solution was stirred at rt for 4 h. Thesolution was concentrated on the rotovap. The residue was puritied viapreparative thin-layer chromatography (10/1 EtOAc/EtOH, SiO₂) to obtain14 mg (17%) of 1BF as a colorless oil. The bis-HCl salt was formed asdescribed above for 6 a. M.p.=206-210° C.

EXAMPLE 2

[0106]

[0107] The aldehyde 2 (0.93 g, 4.0 mmol), piperidino-piperazine 3 (1.0g, 3.4 mmol), and Na(AcO)₃BH (860 mg, 4.0 mmol) were taken up in CH₂Cl₂.(10 ml) and stirred at 25° C. for 18 h. The solution was diluted withCH₂Cl₂ and washed with 1 N NaOH. The aqueous layer was extracted withCH₂Cl₂. The combined organic layers were dried (Na₂SO₄), filtered, andconcentrated. Purifification via flash chromatography (acetone/CH₂Cl₂gradient 2/5-3/5, SiO₂) gave 1.24 g (71%) of 7 as a colorless oil.

[0108] Compound 7 was treated according to the procedures in Steps 4 and5 of Example 1 to obtain the title compound. HRMS (MH⁺) found: 507.3122.

[0109] Using a similar procedure and the appropriate reagents, compoundsof the structure

were prepared, wherein R¹and R⁶ are as defined in the following table:Ex. R¹ R⁶ HRMS (MH⁺) found 2A H CH₃ 429.3340 2B 4-CH₃OC₆H₄CH₂ CH₃548.3838 2C CF₃SO₂ CH₃ 561.2840 2D C₆H₅C(O) CH₃ 533.3611 2E 4-CH₃C₆H₄SO₂CH₃ 583.3442

EXAMPLE 3

[0110]

[0111] The alcohol 1 (2.0 g, 17.4 mmol), N-Boc-4-piperidone 11 (3.5 g,17.4 mmol) and Ti(OiPr)₄ (5.7 ml, 19 mmol) were taken up in CH₂Cl₂ (60ml) and stirred at 25° C. for 64 h. Diethyl aluminum cyanide (42 ml of a1.0 M solution in toluene, 42 mmol) was added to the reaction mixture at25° C. The solution was stirred at 25° C. for an additional 24 h. Thesolution was poured in a flask containing EtOAc and sat. aqueous NaHCO₃at 0° C. The mixture was filtered through a plug of Celite. The layerswere separated, and the aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with brine and dried (Na₂SO₄).Filtration and concentration gave the crude cyanide (4.87 g, 87%) as ayellow oil.

[0112] The cyanide (4.87 g, 15 mmol) was taken up in THF (75 ml).CH₃MgBr (25 ml of a 3.0 M solution in Et₂O) was added to the reactionmixture at 0° C. The solution was allowed to warm to 25° C. and wasstirred at that temperature for 18 h. The solution was partitionedbetween 25 wt % aqueous solution of sodium citrate and EtOAc. Theaqueous layer was extracted with EtOAc. The combined EtOAc layers werewashed with brine and dried (Na₂SO₄). Filtration and concentration gavea yellow oil. Purification via flash chromatography (95/5 to 90/10EtOAc/MeOH. SiO₂) gave 3.7 g (79%) of the piperidino-piperidine 12 as ayellow gum.

[0113] DMSO (1.26 ml, 17.8 mmol) was taken up in CH₂Cl₂ (140 ml). Thesolution was cooled to −40° C. (CH₃CN/CO₂). Oxalyl chloride (1.6 ml,17.8 mmol) was added dropwise to the solution at −40° C. The solutionwas stirred at that temperature for 0.75 h. The alcohol 12 (3.7 g, 11.9mmol) in CH₂Cl₂ was added to the reaction mixture at −40° C. Theresulting solution was stirred at that temperature for 0.75 h. Et₃N (5.0ml, 35.7 mmol) was added to the reaction mixture at −40° C. The whiteslurry was stirred at −40° C. for 0.5 h. The mixture was diluted withCH₂Cl₂ and washed with 1 N NaOH. The aqueous layer was extracted withCH₂Cl₂. The combined organic layers were dried (Na₂SO₄), filtered, andconcentrated to obtain 3.5 g (95%) of aldehyde 13 as a yellow oil.

[0114] The piperazine 14 a (133 mg, 0.65 mmol), aldehyde 13 (200 mg,0.65 mmol), and Na(AcO)₃BH (165 mg, 0.78 mmol) were taken up in CH₂Cl₂and stirred at 25° C. for 20 h. The solution was diluted with CH₂Cl₂ andwashed with 1 N NaOH. The aqueous layer was extracted with CH₂Cl₂. Thecombined CH₂Cl₂ layers were dried (Na₂SO₄), filtered, and concentrated.Purification via preparative thin-layer chromatography (1/1hexanes/acetone, SiO₂) gave 160 mg (46%) of 15 a as an oil.

[0115] The Boc group in 15 a was removed, and the resulting piperidinewas coupled to the pyrimidine acid as described in Scheme A, Step 4, toobtain the title compound as an oil: HRMS (MH⁺) found: 535.3765.

[0116] Other R¹ derivatives can be prepared via deprotection of the4-methoxy benzyl group and subsequent derivatization as describedpreviously in Scheme A.

EXAMPLE 4

[0117]

[0118] Step 1

[0119] N-Boc-(S)-methyl piperazine 40 (4.35 g, 21 .8mmol), benzaldehyde(2.2 ml, 22 mmol), and benzotriazole (2.59 g, 21.8 mmol) were taken upin benzene and heated to reflux with removal of water (Dean-Stark trap).After heating at 110° C. for 4 h, the solution was cooled andconcentrated to furnish 8.9 g (Quant.) of the benzotriazole adduct 41 asa foam.

[0120] Step 2

[0121]41 (1.4 g, 3.4 mmol) was taken up in THF (25 ml). A THF solutionof the piperidinyl grignard (13.7 ml of a 1.0 M solution) was added to41 at 25° C. The solution was stirred at that temperature for 5 h. Thereaction mixture was poured into a separatory funnel containing EtOAcand 25 wt % sodium citrate. The aqueous solution was extracted withEtOAc. The combined EtOAc layers were washed with brine and dried(Na₂SO₄). Filtration and concentration gave a yellow oil. Purificationvia flash chromatography (15/1 CH₂Cl₂/7N NH₃ in CH₃OH, SiO₂) gave 954 mg(72%) of the piperazine-piperidine 42 as a mixture of isomers.

[0122] Step 3

[0123]42 (954 mg, 2.46 mmol) was taken up in CH₃OH (15 ml), and 3 ml ofa 4.0 M HCl solution in dioxane was added. The solution was stirred at25° C. for 18 h, then concentrated to give deprotected piperazine as theHCl salt. The crude salt (2.46 mmol) was partitioned between EtOAc andwater. K₂CO₃ (2.0 grams, 14. 8 mmol) and allyl chloroformate (0.34 ml,3.2 mmol) were added to the mixture. The mixture was stirred vigorouslyat 25° C. for 20 h. The aqueous layer was extracted with EtOAc, thecombined EtOAc layers were washed with brine and dried (Na₂SO₄).Filtration and concentration gave the allyloxycarbonyl (Alloc) protectedpiperazine 43 as a mixture of isomers.

[0124] Step 4

[0125]43 was taken up in 1,2-dichloroethane. 1-Chloro-ethylchloroformate (0.5 ml, 4.9 mmol) and polystyrene bound Hunig's base(PS-DIEA; DIEA is diisopropyl-ethylamide) (2.7 g) were heated at 90° C.for 1.5 h. The solution was cooled and concentrated. The residue wastaken up in CH₃OH and refluxed for 1 h. The solution was concentrated,and the residue was partitioned between CH₂Cl₂ and 1 N NaOH_((aq)). Theaqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried (Na₂SO₄), filtred and concentrated to give 752 mg (85%) of 44as a mixture of isomers.

[0126] Step 5

[0127]44 (752 mg, 2.10 mmol), di-t-butyl-dicarbonate (550 mg, 2.5 mmol),and K₂CO₃ (870 mg, 6.3 mmol) were partitioned between EtOAc and H₂O. Theaqueous layer was extracted with EtOAc. the combined EtOAc layers werewashed with brine and dried with Na₂SO₄. Filtration and concentrationgave the crude N-Boc piperidine 45 as a yellow oil. Purification viaflash chromatography (4/1 hexanes/EtOAc, SiO₂) gave 606 mg (63%) of 45as a colorless foam.

[0128] Step 6

[0129]45 (606 mg, 1.3 mmol), Et₂NH (2.7 ml, 26.5 mmol), and3,3′,3″-phosphinidyne-tris(benzenesulfonic acid), trisodium salt (30 mg,0.052 mmol) were taken up in CH₃CN/H₂O (1/1 40 ml). Pd(OAc)₂ (6 mg,0.026 mmol) was added and the solution was stirred at 25° C. for 3 h.The solution was concentrated, and the residue was partitioned betweenEtOAc and 1 N NaOH_((aq.)). The aqueous layer was extracted with EtOAc,the combined organic layers were washed with brine and dried (Na₂SO₄).Filtration and concentration gave 500 mg (99%) of 46 as a mixture ofisomers.

[0130] Step 7

[0131]46 (500 mg, 1.3 mmol), p-anisaldehyde (1.2 ml, 1.6 mmol), andNa(AcO)₃BH (340 mg, 1.6 mmol) were taken up in CH₂Cl₂ and stirred at 25°C. (18 h). The solution was diluted with CH₂Cl₂ and washed with 1 NNaOH_((aq.)). The aqueous layer was extracted with CH₂Cl₂, the combinedorganic layers were dried (Na₂SO₄), filtered and concentrated to givethe crude p-methoxybenzyl (PMB) protected piperazine 47 as a mixture ofisomers. Purification via flash chromatography (6/1 hexanes/EtOAc, SiO₂)gave 713 mg of 47 as a semisolid (mixture of isomers). Purification viarecrystallization (hexanes/CH₂Cl₂) gave 220 mg (34%) of the (S,S) isomer47 as white needles.

[0132] Step 8

[0133]47 (220 mg, 0.45 mmol) and 4.0 M HCl in dioxane (2 ml) were takenup in CH₃OH and stirred at 25° C. (4 h). The solution was concentrated,and the residue was partitioned between CH₂Cl₂ and 1 N NaOH_((aq.)). Theaqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried (Na₂SO₄). Filtration and concentration gave 182 mg (100%) of48 as a colorless oil.

[0134] Step 9

[0135]48 was derivatized into 49 using the procedure of Example 3, Step1.

[0136] Step 10

[0137] The Boc group in 49 was removed (HCl), and the resultingpiperidine was coupled to the pyrimidine acid as described in Scheme Ato furnish the title compound as a yellow oil: HRMS(MH⁺) found:625.4235.

[0138] Using similar procedures and the appropriate reagents, compoundsof the structure

[0139] were prepared, where R¹ is defined in the following table: HRMS(MH⁺) Ex. R¹ found 4A CH₃SO₂ 583.3419 4B 3-Cl—C₆H₄SO₂ 679.3204

EXAMPLE 5

[0140]

Step 1:

[0141] Compound 3 (2 g, 6.7 mmol), allyl chloroformate (0.93 ml, 8.7mmol), and K₂CO₃ (5.6 g, 40 mmol) were partitioned between EtOAc andH₂O. The mixture was stirred vigorously at 25° C. (24 h). The layerswere separated, and the aqueous layer was extracted with EtOAc. Thecombined EtOAc layers were washed with brine and dried (Na₂SO₄).Filtration and concentration gave 2.6 g (100%) of the alloc protectedpiperazine as a thick yellow oil.

[0142] The Boc group was removed, and the resulting piperidinewascoupled to the pyrimidine acid as described in Scheme A, Step 4, toobtain 2.3 g (85% from 3) of the piperidine-amide 50 as a yellow foam.

[0143] The Alloc group in 50 was removed according to the conditionsdescribed for the conversion of 45 to 46 above in Example 4 whichfurnished piperazine 51.

[0144]51 (450 mg, 1.36 mmol), imidoyl chloride 52 (360 mg, 1.36 mmol),and iPr₂NEt (1.2 ml, 6.8 mmol) were taken up in CH₂Cl₂ and stirred at25° C. (18 h). The solution was diluted with CH₂Cl₂ and washed withwater. The aqueous layer was extracted with CH₂Cl₂. The combined organiclayers were dried (Na₂SO₄). Filtration and concentration gave the crudeamide-oxime 53. Purification via preparative thin-layer chromatography(95/5 EtOAc/Et₃N, SiO₂) gave 550 mg (72%) of amide-oxime 53 as a mixtureof isomers.

[0145]53 (550 mg, 0.99 mmol), EtI (0.16 ml, 1.98 mmol), and Bu₄NHSO₄ (3mg, 0.01 mmol) were partitioned between toluene and aqueous 50% NaOH.The mixture was stirred vigorously at 25° C. (18 h). The mixture wasdiluted with EtOAc and water. The aqueous layer was extracted withEtOAc. The combined organic layers were washed with brine and dried(Na₂SO₄). Filtration and concentration gave a yellow oil. Purificationvia preparative thin-layer chromatography (95/5 EtOAc/Et₃N, SiO2) gave457 mg (79%) of 54 as a yellow oil (mixture of isomers).

[0146] Step 5

[0147] The Boc group in 54 was removed by HCl as described in Scheme A,Step 4. The resulting piperidine was reacted with 3-chlorobenzenesulfonyl chloride, according to the procedure described in Example 1,Step 5, second paragraph, to obtain Example 5 as a yellow oil. HRMS(MH⁺): 660.3089.

[0148] Using similar procedures and the appropriate reagents, compoundsof the structure

[0149] were prepared, where R¹ is defined in the following table: HRMS(MH⁺) Ex. R¹ found 5A 4-CH₃OC₆H₄SO₂ 656.3588 5B CH₃SO₂ 564.3328

[0150] The following assays can be used to determine the CCR5 inhibitoryand antagonistic activity of the compounds of the invention.

[0151] CCR5 Membrane Binding Assay

[0152] A high throughput screen utilizing a CCR5 membrane binding assayidentifies inhibitors of RANTES binding. This assay utilizes membranesprepared from NIH 3T3 cells expressing the human CCR5 chemokine receptorwhich have the ability to bind to RANTES, a natural ligand for thereceptor. Using a 96-well plate format, membrane preparations areincubated with ¹²⁵I-RANTES in the presence or absence of compound forone hour. Compounds are serially diluted over a wide range of 0.001ug/ml to 1 ug/ml and tested in triplicates. Reaction cocktails areharvested through glass fiber filters, and washed thoroughly. Totalcounts for replicates are averaged and data reported as theconcentration required to inhibit 50 percent of total ¹²⁵I-RANTESbinding. Compounds with potent activity in the membrane binding assayare further characterized in seconday cell-based HIV-1 entry andreplication assays.

[0153] HIV-1 Entry Assay

[0154] Replication defective HIV-1 reporter virions are generated bycotransfection of a plasmid encoding the NL4-3 strain of HIV-1 (whichhas been modified by mutation of the envelope gene and introduction of aluciferase reporter plasmid) along with a plasmid encoding one ofseveral HIV-1 envelope genes as described by Connor et al, Virology, 206(1995), p. 935-944. Following transfection of the two plasmids bycalcium phosphate precipitation, the viral supernatants are harvested onday 3 and a functional viral titer determined. These stocks are thenused to infect U87 cells stably expressing CD4 and the chemokinereceptor CCR5 which have been preincubated with or without testcompound. Infections are carried out for 2 hours at 37° C., the cellswashed and media replaced with fresh media containing compound. Thecells are incubated for 3 days, lysed and luciferase activitydetermined. Results are reported as the concentration of compoundrequired to inhibit 50% of the luciferase activity in the controlcultures.

[0155] HIV-1 Replication Assay

[0156] This assay uses primary peripheral blood mononuclear cells or thestable U87-CCR5 cell line to determine the effect of anti-CCR5 compoundsto block infection of primary HIV-1 strains. The primary lymphocytes arepurified from normal healthy donors and stimulated in vitro with PHA andIL-2 three days prior to infection. Using a 96-well plate format, cellsare pretreated with drug for 1 hour at 37° C. and subsequently infectedwith an M-tropic HIV-1 isolates. Following infection, the cells arewashed to remove residual inoculum and cultured in the presence ofcompound for 4 days. Culture supernatants are harvested and viralreplication measured by determination of viral p24 antigenconcentration.

[0157] Calcium Flux Assay

[0158] Cells expressing the HIV coreceptor CCR5 are loaded with calciumsensitive dyes prior to addition of compound or the natural CCR5 ligand.Compounds with agonist properties will induce a calcium flux signal inthe cell, while CCR5 antagonists are identified as compounds which donot induce signaling by themselves but are capable of blocking signalingby the natural ligand RANTES.

[0159] GTPγS Binding Assay (Secondary Membrane Binding Assay)

[0160] A GTPγS binding assay measures receptor activation by CCR5ligands. This assay measures the binding of ³⁵S labeled-GTP to receptorcoupled G-proteins that occurs as a result of receptor activation by anappropriate ligand. In this assay, the CCR5 ligand, RANTES, is incubatedwith membranes from CCR5 expressing cells and binding to the receptoractivation (or binding) is determined by assaying for bound ³⁵S label.The assay quantitatively determines if compounds exhibit agonistcharacteristics by inducing activation of the receptor or alternativelyantagonist properties by measuring inhibition of RANTES binding in acompetitive or non-competitive fashion.

[0161] Chemotaxis Assay

[0162] The chemotaxis assay is a functional assay which characterizesthe agonist vs. antagonist properties of the test compounds. The assaymeasures the ability of a non-adherent murine cell line expressing humanCCR5 (BaF-550) to migrate across a membrane in response to either testcompounds or natural ligands (i.e., RANTES, MIP-1β). Cells migrateacross the permeable membrane towards compounds with agonist activity.Compounds that are antagonists not only fail to induce chemotaxis, butare also capable of inhibiting cell migration in response to known CCR5ligands.

[0163] The role of CC chemokine receptors such as CCR-5 receptors ininflammatory conditions has been reported in such publications asImmunology Letters, 57, (1997), 117-120 (arthritis); Clinical &Experimental Rheumatology, 17 (4) (1999), p. 419-425 (rheumatoidarthritis); Clinical & Experimental Immunology, 117 (2) (1999),p.237-243 (atopic dermatitis); International Journal oflmmunopharmacology, 20 (11) (1998), p. 661-7 (psoriasis); Journal ofAllergy & Clinical Immunology, 100 (6, Pt 2) (1997), p. S52-5 (asthma);and Journal of Immunology, 159 (6) (1997), p. 2962-72 (allergies).

[0164] In the assay to determine HIV replication, compounds of theinvention range in activity from an IC₅₀ of about 0.1 to about 1000 nM,with preferred compounds having a range of activity from about 0.1 toabout 100 nM, more preferably about 0.1 to about 10 nM.

[0165] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0166] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0167] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

[0168] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0169] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0170] Preferably the compound is administered orally.

[0171] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

[0172] The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 10 mg to about 500 mg, preferably fromabout 25 mg to about 300 mg, more preferably from about 50 mg to about250 mg, and most preferably from about 55 mg to about 200 mg, accordingto the particular application.

[0173] The actual dosage of the compound of formula I employed may bevaried depending upon the requirements of the patient and the severityof the condition being treated. Determination of the proper dosageregimen for a particular situation is within the skill of the art. Forconvenience, the total daily dosage may be divided and administered inportions during the day as required.

[0174] The amount and frequency of administration of the compounds ofthe invention and/or the pharmaceutically acceptable salts thereof willbe regulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 100mg/day to about 300 mg/day, preferably 150 mg/day to 250 mg/day, morepreferably about 200 mg/day, in two to four divided doses.

[0175] The doses and dosage regimens of the NRTIs, NNRTIs, PIs and otheragents used in combination with the CCR5 antagonist compound will bedetermined by the attending clinician inview of the approved doses anddosage regimens in the package inserts or as set forth in the protocols,taking into consideration the age, sex and condition of the patient andthe severity of the condition treated.

[0176] The goal of the HIV-1 therapy of the present invention is toreduce the HIV-1-RNA viral load below the detectable limit. The“detectable limit of HIV-1-RNA” in the context of the present inventionmeans that there are fewer than about 200 to fewer than about 50 copiesof HIV-1-RNA per ml of plasma of the patient as measured byquantitative, multi-cycle reverse transcriptase PCR methodology. HIV-1-RNA is preferably measured in the present invention by the methodologyof Amplicor -1 Monitor 1.5 (available from Roche Diagnostics) or ofNuclisens HIV-1 QT-1.

[0177] While the present invention has been described in conjunctionwith the specific embodiments set forth above, many alternatives,modifications and variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

What is claimed is:
 1. A compound represented by the structural formulaI

or a pharmaceutically acceptable salt or isomer thereof, wherein: Q, Xand Z are independently selected from the group consisting of CH and N,provided that one or both of Q and Z is N; R, R⁴, R⁵, R⁶ and R⁷ areindependently selected from the group consisting of H and (C₁-C₆)alkyl;R¹ is H, (C₁-C₆)alkyl, fluoro-(C₁-C₆)alkyl-, R⁹-aryl(C₁-C₆)alkyl-,R⁹-heteroaryl-(C₁-C₆)alkyl-, (C₁-C₆)alkyl-SO₂—, (C₃-C₆)cycloalkyl—SO₂—,fluoro-(C₁-C₆)alkyl—SO₂—, R⁹-aryl—SO₂—, R⁹-heteroaryl—SO₂—,N(R²²)(R²³)—SO₂—, (C₁-C₆)alkyl-C(O)—, (C₃-C₆)cyclo-alkyl—C(O)—,fluoro-(C₁-C₆)alkyl—C(O)—, R⁹-aryl—C(O)—, NH—(C₁-C₆)alkyl—C(O)— orR⁹-aryl—NH—C(O)—; R² is H or (C₁-C₆)alkyl, and R³ is H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl-, (C₃-C₁₀)-cycloalkyl-,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-, R⁹-aryl, R⁹-aryl(C₁-C₆)-alkyl-,R⁹-heteroaryl, or R⁹-heteroaryl(C₁-C₆)alkyl-, provided that both X and Zare not each N; or R² and R³ together are ═O, ═NOR¹⁰, ═N—NR¹¹R¹² or═CH(C₁-C₆)alkyl, provided that when one or both of X and Z is N, R² andR³ together are not ═CH(C₁-C₆)alkyl; and when X and Z are each CH, R³can also be (C₁-C₆)alkoxy, R⁹-aryloxy, R⁹-heteroaryloxy,(C₁-C₆)alkyl—C(O)O—, (C₁-C₆)alkyl—NH—C(O)O—, N((C₁-C₆)alkyl)₂—C(O)O—,(C₁-C₆)alkyl—C(O)—NR¹³—, (C₁-C₆)alkyl—O—C(O)—NR¹³—,(C₁-C₆)alkyl—NH—C(O)—NR¹³— or N((C₁-C₆)alkyl)₂—C(O)—NR¹³—; R⁸ is (R¹⁴,R¹⁵, R¹⁶)-substituted phenyl, (R¹⁴, R¹⁵, R¹⁶)-substituted 6-memberedheteroaryl, (R¹⁴, R¹⁵, R¹⁶)-substituted 6-membered heteroaryl N-oxide,(R¹⁷, R¹⁸)-substituted 5-membered heteroaryl, naphthyl, fluorenyl,diphenylmethyl,

R⁹ is 1, 2 or 3 substituents independently selected from the groupconsisting of H, halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, —OCF₃,CH₃C(O)—, —CN, CH₃SO₂—, CF₃SO₂— and —N(R²²)(R²³); R¹⁰ is H,(C₁-C₆)alkyl, fluoro(C₁-C₆)alkyl-, (C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-,hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkyl-O—(C₂-C₆)alkyl-,(C₁-C₆)alkyl—O—C(O)—(C₁-C₆)alkyl- or N(R²²)(R²³)—C(O)—(C₁-C₆)alkyl-; R¹¹and R¹² are independently selected from the group consisting of H,(C₁-C₆)alkyl and (C₃-C₁₀)cycloalkyl, or R¹¹ and R¹² together are C₂-C₆alkylene and form a ring with the nitrogen to which they are attached;R¹⁴ and R¹⁵ are independently selected from the group consisting of(C₁-C₆)alkyl, halogen, —NR²²R²³, —OH, —CF₃, —OCH₃, —O—acyl and —OCF_(3;)R¹⁶ is R¹⁴, hydrogen, phenyl, —NO₂, —CN, —CH₂F, —CHF₂, —CHO, —CH═NOR²⁴,pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R²⁴)CONR²⁵R²⁶,—NHCONH(chloro-(C₁-C₆)alkyl), —NHCONH ((C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl),—NHCO(C₁-C₆)alkyl, —NHCOCF₃, —NHSO₂N(R²²)(R²³), —NHSO₂(C₁-C₆)alkyl,—N(SO₂CF₃)₂, —NHCO₂—(C₁-C₆)alkyl, C₃-C₁₀cycloalkyl, —SR²⁷, —SOR²⁷,—SO₂R²⁷, —SO₂NH(R²²), —OS₂(C₁-C₆)alkyl, —OSO₂CF₃, hydroxy(C₁-C₆)alkyl-,—CON R²⁴R²⁵, —CON(CH₂CH₂OCH₃)₂, —OCONH(C₁-C₆)alkyl, —CO₂R²⁴, —Si(CH₃)₃or —B(OC(CH₃)₂)_(2;) R¹⁷ is (C₁-C₆)alkyl, —N(R²²)(R²³) or R¹⁹-phenyl;R¹³, R¹⁸, R²², R²³, R²⁴, R²⁵ and R²⁶ are independently selected from thegroup consisting of H and (C₁-C₆)alkyl; R¹⁹ is 1, 2 or 3 substituentsindependently selected from the group consisting of H, (C₁-C₆)alkyl,—CF₃, —CO₂R²⁵, —CN, (C₁-C₆)alkoxy and halogen; R²⁰ and R²¹areindependently selected from the group consisting of H and (C₁-C₆)alkyl,or R²⁰ and R²¹together with the carbon to which they are attached form aspiro ring of 3 to 6 carbon atoms; and R²⁷ is (C₁-C₆)alkyl or phenyl. 2.A compound of claim 1 wherein Z is CH, and Q and X are each N.
 3. Acompound of claim 1 wherein R¹ is R⁹-aryl(C₁-C₆)alkyl-,R⁹-heteroaryl-(C₁-C₆)alkyl-, (C₁-C₆)alkyl-SO₂—, (C₃-C₆)cycloalkyl-SO₂—,fluoro-(C₁-C₆)-alkyl—SO₂—, R⁹-aryl—SO₂—, or R⁹-aryl—NH—C(O)—.
 4. Acompound of claim 1 wherein R² is hydrogen and R³ is (C₁-C₆)alkyl,R⁹-aryl, R⁹-aryl(C₁-C₆)-alkyl, R⁹-heteroaryl, orR⁹-heteroaryl(C₁-C₆)alkyl.
 5. A compound of claim 1 wherein R, R⁵ and R⁷are each hydrogen and R⁶ is —CH₃.
 6. A compound of claim 1 wherein X isN and R⁴ is methyl.
 7. A compound of claim 1 wherein X is CH and R⁴ isH.
 8. A compound of claim 1 wherein R⁹ is H, halogen, (C₁-C₆)alkyl or(C₁-C₆)alkoxy.
 9. A compound of claim 1 wherein R⁸ is (R¹⁴, R¹⁵,R¹⁶)-phenyl; (R¹⁴, R¹⁵, R¹⁶)-pyridyl or an N-oxide thereof; or (R¹⁴,R¹⁵, R¹⁶)-pyrimidyl.
 10. A compound of claim 8 wherein R⁸is


11. A compound of claim 10 wherein R¹⁴ and R¹⁵ are independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen and NH₂, andR¹⁶ is H.
 12. A compound of claim 1 selected from the group consistingof compounds of the formula

R¹ R³ R⁶ 4-CH₃OC₆H₄CH₂ C₆H₅ CH₃ CH₃SO₂ C₆H₅ CH₃ 4-CH₃OC₆H₄CH₂ CH₂C₆H₅CH₃ CH₃SO₂ CH₂CH₂CH₃ CH₃ 4-CH₃C₆H₄SO₂ CH₂CH₂CH₃ CH₃ 4-CH₃C₆H₄SO₂ C₆H₅CH₃ C₆H₅NHC(O) C₆H₅ CH₃ 4-CH₃OC₆H₄CH₂ C₆H₅ H 4-CH₃OC₆H₄SO₂ C₆H₅ CH₃3-Cl—C₆H₄SO₂ C₆H₅ CH₃ CH₃SO₂ CH₂C₆H₅ CH₃ 3-Cl—C₆H₄SO₂ CH₂C₆H₅ CH₃CH₃CH₂SO₂ CH₂C₆H₅ CH₃ 4-CH₃OC₆H₄SO₂ 4-F—C₆H₄ CH₃ CH₃SO₂ 4-F—C₆H₄ CH₃3-Cl—C₆H₄SO₂ 4-F—C₆H₄ CH₃ CF₃C(O) 4-F—C₆H₄CH₂ CH₃ CH₃SO₂ 3-F—C₆H₄ CH₃3-Cl—C₆H₄SO₂ 3-F—C₆H₄ CH₃ 4-CH₃OC₆H₄SO₂ 3-F—C₆H₄ CH₃ CH₃SO₂ 4-F—C₆H₄CH₂CH₃ 3-Cl—C₆H₄SO₂ 4-F—C₆H₄CH₂ CH₃ 4-CH₃OC₆H₄SO₂ 4-F—C₆H₄CH₂ CH₃4-CH₃OC₆H₄CH₂ 2-thienyl CH₃ CF₃CH₂SO₂ C₆H₅ CH₃ CF₃SO₂ C₆H₅ CH₃4-CH₃OC₆H₄CH₂ 3-thienyl CH₃ 3-Cl—C₆H₄SO₂ 2-thienyl CH₃ 4-CH₃OC₆H₄SO₂2-thienyl CH₃ CH₃SO₂ 2-thienyl CH₃ CH₃SO₂ 3-thienyl CH₃ 3-Cl—C₆H₄SO₂3-thienyl CH₃ 4-F—C₆H₄SO₂ CH₂C₆H₅ CH₃ 2-thienyl-SO₂ CH₂C₆H₅ CH₃ C₆H₅SO₂CH₂C₆H₅ CH₃ CF₃SO₂ CH₂C₆H₅ CH₃ CF₃CH₂SO₂ CH₂C₆H₅ CH₃ (CH₃)₂NSO₂ CH₂C₆H₅CH₃ cyclopropyl-SO₂ 3-F—C₆H₄ CH₃ 4-F—C₆H₄SO₂ 3-F—C₆H₄ CH₃ 4-CH₃OC₆H₄CH₂n-Butyl CH₃ 3-Cl—C₆H₄SO₂ n-Butyl CH₃ 4-CH₃OC₆H₄SO₂ n-Butyl CH₃3-Cl—C₆H₄SO₂ 3-pyridyl CH₃ 4-CH₃OC₆H₄SO₂ 3-pyridyl CH₃ 3-Cl—C₆H₄SO₂2-pyridyl CH₃ cyclopropyl-SO₂ C₆H₅ CH₃ CH₃CH₂SO₂ C₆H₅ CH₃ CH₃CH₂CH₂SO₂C₆H₅ CH₃ i-propyl-SO₂ C₆H₅ CH₃ CH₃C(O) C₆H₅ CH₃ cyclopropyl-C(O) C₆H₅CH₃ CH₃CH₂C(O) C₆H₅ CH₃ i-propyl-C(O) C₆H₅ CH₃ 4-CH₃OC₆H₄CH₂3,5-difluorophenyl CH₃ cyclopropyl-SO₂ 3,5-difluorophenyl CH₃ CH₃SO₂cyclohexyl CH₃


13. A compound of claim 1 selected from the group consisting of


14. A pharmaceutical composition comprising an effective amount of acompound of claim 1 in combination with a pharmaceutically acceptablecarrier.
 15. A pharmaceutical composition comprising an effective amountof a compound of claim 1, in combination with one or more antiviral orother agents useful in treating HIV, or in combination with with one ormore agents useful in treating treating solid organ transplantrejection, graft v. host disease, arthritis, rheumatoid arthritis,inflammatory bowel disease, atopic dermatitis, psoriasis, asthma,allergies or multiple sclerosis, in combination with a pharmaceuticallyacceptable carrier.
 16. A method of treating Human Immuno-deficiencyVirus comprising administering to a mammal inneed of such treatment aneffective amount of a compound of claim
 1. 17. A method of treatingHuman Immuno-deficiency Virus comprising administering to a mammalinneed of such treatment an effective amount of a compound of claim 1 incombination with one or more antiviral or other agents useful in thetreatment of Human Immuno-deficiency Virus
 18. A method of treatingsolid organ transplant rejection, graft v. host disease, arthritis,rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis,psoriasis, asthma, allergies or multiple sclerosis, comprisingadministering to a mammal in need of such treatment an effective amountof a compound of claim
 1. 19. A method of treating solid organtransplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis, comprising administering to amammal in need of such treatment an effective amount of a compound ofclaim 1 in combination with one or more agents useful in the treatmentof solid organ transplant rejection, graft v. host disease, arthritis,rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis,psoriasis, asthma, allergies or multiple sclerosis.
 20. A kit comprisingin separate containers in a single package pharmaceutical compositionsfor use in combination to treat Human Immunodeficiency Virus whichcomprises in one container a pharmaceutical composition comprising aneffective amount of a compound of claim 1 in a pharmaceuticallyacceptable carrier, and in separate containers, one or morepharmaceutical composition comprising an effective amount of a antiviralor other agent useful in the treatment of Human Immunodeficiency Virusin a pharmaceutically acceptable carrier.